Multiple biological cofactors have been shown to increase a woman's susceptibility to HIV-1 infection, including sexually transmitted diseases, vaginal flora, hormonal contraceptive use and pregnancy. Many of these factors cause inflammation or immune activation, suggesting a possible mechanism for their affect on HIV-1 susceptibility. The proposed aims of this project will test the hypothesis that innate immune conditions, including immune activation and inflammation, impact HIV-1 susceptibility in women. The foundation for this hypothesis comes from many observations, including the above-mentioned results suggesting that several of the biological cofactors for HIV-1 acquisition alter innate immunity, the fact that immune activation is known to make CD4+T lymphocytes more permissive to infection, and the fact that immune activation early in HIV-1 infection appears to fuel virus replication and disease progression. Although there are several lines of support for this hypothesis, the association between inflammation or immune activation has never been directly examined in relation to risk of HIV-1 acquisition in women. We propose to test this hypothesis by examining cytokine profiles, which provide a surrogate marker of innate immune conditions, just prior to the time of HIV-1 infection, in relation to risk of HIV-1 infection in several populations. The cohorts for these studies will include a 14 year seroincident female cohort in Mombasa, Kenya and a cohort of pregnant women in Nairobi, Kenya. We will take advantage of banked samples and clinical data from the Mombasa cohort as well as samples and data collected as part of Projects 1 and 2 to address the Aims of Project 3. This integration with long-term cohort studies by our group and with the new studies in other Projects will provide considerable opportunities for synergy among projects in the program grant. It will also permit a comprehensive study of innate immune factors at the time of HIV-1 acquisition across multiple high-risk cohorts that will include women with various biological cofactors of importance in determining risk of HIV-1 acquisition in women. RELEVANCE (See instructions): These studies will provide critical data on the characteristics of the innate immune response that impact risk of HIV-infection in women, including women in multiple high-risk groups. In addition, the study is designed to identify a cytokine profile that is associated with increase risk of HIV acquisition in women. This profile may provide a useful surrogate marker for monitoring the impact of new prevention methods, particularly microbicides.